Enhancement of Effectiveness of 5-Fluorouracil in Treatment of Tumor Metastases and Cancer

ABSTRACT

Tumor growth and metastases in cancer patients are inhibited by administration of a combination therapy including effective amounts of 5-Fluorouracil and a methylol transfer agent such as taurolidine, taurultam or mixtures thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of pending U.S. applicationSer. No. 10/660,798, filed Sep. 12, 2003, which is acontinuation-in-part of U.S. application Ser. No. 10/281,138, filed Oct.28, 2002, now U.S. Pat. No. 6,815,441, which is a continuation-in-partof U.S. application Ser. No. 09/993,896, filed Nov. 27, 2001, whichclaims the benefit of U.S. Provisional Application No. 60/253,138, filedNov. 28, 2000. U.S. application Ser. No. 10/281,138 is a divisional ofU.S. application Ser. No. 09/583,902, filed Jun. 1, 2000, now U.S. Pat.No. 6,479,481 B1, which claims the benefit of U.S. ProvisionalApplication No. 60/182,200, filed Feb. 14, 2000, U.S. ProvisionalApplication No. 60/174,607, filed Jan. 5, 2000, U.S. ProvisionalApplication No. 60/167,681, filed Nov. 29, 1999, U.S. ProvisionalApplication No. 60/151,050, filed Aug. 27, 1999 and U.S. ProvisionalApplication No. 60/137,421, filed Jun. 4, 1999.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the field of treating tumor metastasesand cancer.

2. Description of the Background Art

5-Fluorouracil (5-FU) is an antineoplastic drug with clinical activityin a variety of tumors, such as cancers of the colon and rectum, headand neck, liver, breast, and pancreas. One problem with 5-Fu is itsextreme toxicity. Since 5-FU targets rapidly dividing cells, the primarytoxic side effects are on bone marrow, intestinal mucousa and oralmucousa. Thus, leukocyte and platelet count decreases substantiallyafter administration. Other side effects include stomatitis, diarrhea,nausea and vomiting. Neurological side effects include somnolence andataxia. Other side effects include chest pain, myocardial necrosis andischemia. Inflammatory reactions such as acute and chronicconjunctivitis leading to tear duct stenosis and ectropion also occur.

Monotherapy with 5-FU only results in tumor remission in about 20-25% ofpatients, and the average remission time is only about 6-8 months.

Although combination chemotherapy with 5-FU and other antineoplasticagents has been proposed, typically no substantive additional benefit isprovided by the other antineoplastic agents over treatment with 5-FUalone.

Thus, there remains a significant need in the art for new and improvedcancer treatment therapies.

SUMMARY OF THE INVENTION

In accordance with the present invention, tumor growth and metastasis isinhibited in a cancer patient by administering to said patient acombination therapy comprising effective amounts of 5-FU and a methyloltransfer agent.

DETAILED DESCRIPTION OF THE INVENTION

It has surprisingly been found that methylol transfer agents such astaurolidine and taurultam substantially enhance or augment theantineoplastic effects of 5-FU in a combination therapy for inhibitingtumor metastases and treating cancer in patients. Such methylol transferagents also substantially reduce the toxic side effects of 5-FU.

5-FU when used in accordance with the present invention includesbiologically active derivatives or substantial equivalents thereof.

Methylol transfer agents include methylol-containing compounds such astaurolidine and taurultam. The compounds taurolidine and taurultam aredisclosed in U.S. Pat. No. 5,210,083. Other suitable methylol-containingcompounds may be found among those identified in PCT Publication No. WO01/39763. Particularly preferred methylol transfer agents forutilization in accordance with the present invention are taurolidine,taurultam, biologically active derivatives thereof and mixtures thereof.

Particularly preferred embodiments involve treatment of cancers selectedfrom the group consisting of colon cancer, rectal cancer and colo-rectalcancer, as well as inhibition of tumor metastases thereof.

Other cancers to which the combination therapy of the present inventionis effective may include other carcinomas, sarcomas or lymphomas,cancers of the head and neck, liver cancer, breast cancer and pancreaticcancer. Cancers to which the present invention may be applicable includeglioma, neuroblastoma, astrocytoma, carcinomatous meningitis, ovariancancer, prostate cancer, central nervous system (CNS) cancer, lungcancer, gastric cancer, esophageal cancer, urinary bladder cancer,leukemia, lymphoma, melanoma, renal cell cancer and metastases thereof.

Effective daily dosage amounts of 5-FU may be in the range of about0.1-1,000 mg per pharmaceutical dosage unit. Effective dosage amounts of5-FU also may be in the range of about 100-5,000 mg/m² body surfacearea, preferably about 200-1,000 mg/m² body surface area, morepreferably about 500-600 mg/m² body surface area. 5-FU typically isprovided in 250 mg or 500 mg ampules for injection, or 250 mg capsulesfor oral administration.

Effective dosage amounts of a methylol transfer agent in accordance withthe present invention may comprise pharmaceutical dosage units withinthe range of about 0.1-1,000 mg/kg. Preferred dosages may be in therange of about 10-20 grams taurolidine, taurultam or a mixture thereof,per administration.

Pharmaceutical dosage units of the combined therapy of the presentinvention may be administered by any suitable route, which include oral,topical or peritoneal administration, e.g., subcutaneously,intraperitoneally, intramuscularly, or intravenously, e.g., by infusionor injection.

In preferred embodiments, 250 ml of taurolidine 2% solution isadministered by intravenous infusion about 1-6 times per day, morepreferably about 2-4 times per day, during a treatment period,concurrently or sequentially with administration of 5-FU at a preferreddosage within the range of about 500-600 mg/m² body surface area. Inaccordance with one embodiment, 5-FU is administered by bolusintravenous injection at a dosage of 500 mg/m² body surface area, 1-3days per week for a total of three weeks, during a treatment periodincluding administration of taurolidine and/or taurultam. In analternative embodiment, a 600 mg/m² intravenous bolus injection isadministered 1-2 times per week during a three week treatment period,along with administration of taurolidine and/or taurultam as indicatedabove.

The present invention also is directed to a combination of 5-FU and amethylol transfer agent, in effective amounts for simultaneous, separateor sequential use for inhibiting tumor metastasis in a cancer patient.The invention also is directed to pharmaceutical combinations includingpharmaceutical dosage units comprising effective amounts of5-Fluorouracil and a methylol transfer agent for inhibiting tumormetastasis in a cancer patient, as well as to pharmaceuticalcompositions comprising such combinations.

In contrast with other antineoplastic agents, methylol transfer agentssuch as taurolidine and taurultam surprisingly and substantially enhanceor augment the antineoplastic effects of 5-FU, and substantially reducethe extreme toxic side effects of 5-FU. Accordingly, with a combinationtherapy of 5-FU and a methylol transfer agent such as taurolidine and/ortaurultam, the amount of 5-FU can be reduced to achieve the sameactivity as larger dosages of 5-FU alone, while encountering fewer toxicside effects. Alternatively, combination therapy in accordance with thepresent invention can be utilized with the same 5-FU dosage levels asmonotherapy with 5-FU, while achieving enhanced antineoplastic resultsalong with fewer side effects.

The invention is further illustrated by the following non-limitingexample.

EXAMPLE 1

The human colo-rectal cell lines SW 480 (primary), SW 620 (metastatic)and W 707 (metastatic) were incubated with the following: culture medium(control), taurolidine at 5, 10, 25, 50 and 100 μg/ml doses, and5-Fluorouracil (5-FU) at 5, 10, 25, 50 and 100 μM doses. 5-FU was testedalone, and together with taurolidine. Cell proliferation, apoptosis andcell cycle were assessed.

There was a significant decrease in tumor cell proliferation at 24hours. There was no significant increase in taurolidine-inducedapoptosis and taurolidine did not alter the phases of the cell cycle.There was an increase in LDH release (p=0.0011), which correlated withinhibited tumor proliferation. Taurolidine was found to augment theeffects of given doses of 5-FU (p=0.0001).

1. A method of inhibiting tumor growth in a cancer patient comprisingadministering to said patient a combination therapy comprising effectiveamounts of 5-Fluorouracil (5-FU) and a methylol transfer agent, saidmethylol transfer agent being capable of substantially enhancingantineoplastic effects of said 5-FU, substantially reducing toxic sideeffects of said 5-FU, or a combination thereof, wherein said methyloltransfer agent has a substantial effect on activity of said 5-FU, saidsubstantial effect being selected from the group consisting ofsubstantially enhancing antineoplastic effects of said 5-FU,substantially reducing toxic side effects of said 5-FU, and acombination thereof, wherein said methylol transfer agent istaurolidine, taurultam or a mixture thereof.
 2. The method of claim 1wherein said tumor is a lymphoma, carcinoma or sarcoma.
 3. The method ofclaim 1 wherein said tumor is a glioma, a neuroblastoma, an astrocytoma,carcinomatous meningitis, breast cancer, ovarian cancer, colon cancer,rectal cancer, colo-rectal cancer, prostate cancer, pancreatic cancer,CNS cancer, liver cancer, lung cancer, gastric cancer, esophagealcancer, urinary bladder cancer, leukemia, melanoma, renal cell cancer,cancer in a patients head, or cancer in a patients neck.
 4. The methodof claim 1 wherein said tumor is colon cancer, rectal cancer orcolo-rectal cancer.
 5. The method of claim 6 wherein said tumor growthis metastatic tumor growth.
 6. The method of claim 7 wherein saidmethylol transfer agent is taurolidine, taurultam or a mixture thereof.7. The method of claim 1 wherein said side effects are selected fromside effects on bone marrow, intestinal mucousa or oral mucousa,leukocyte or platelet count decreases, stomatitis, diarrhea, nausea,vomiting, neurological side effects, somnolence, ataxia, chest pain,myocardial necrosis, ischemia, inflammatory reactions, acute or chronicconjunctivitis, or tear duct stenosis or ectropion.
 8. The method ofclaim 1 wherein said agent is administered at a dosage of about0.1-1,000 mg/kg.
 9. The method of claim 1 wherein said agent isadministered at a dosage of about 10-20 grams.
 10. The method of claim 1wherein said 5-FU is administered at a dosage of about 0.1-1,000 mg. 11.The method of claim 1 wherein said 5-FU is administered at a dosage ofabout 100-5,000 mg/m² body surface area.
 12. The method of claim 1wherein said 5-FU is administered at a dosage of about 200-1,000 mg/m²body surface area.
 13. The method of claim 1 wherein said 5-FU isadministered at a dosage of about 500-600 mg/m² body surface area. 14.The method of claim 1 wherein said 5-FU is administered at a dosage ofabout 250 mg or 500 mg.
 15. A combination comprising 5-FU and a methyloltransfer agent in effective amounts for simultaneous, separate orsequential use for inhibiting tumor growth in a cancer patient, saidmethylol transfer agent being capable of substantially enhancingantineoplastic effects of said 5-FU, substantially reducing toxic sideeffects of said 5-FU, or a combination thereof, wherein said methyloltransfer agent has a substantial effect on activity of said 5-FU, saidsubstantial effect being selected from the group consisting ofsubstantially enhancing antineoplastic effects of said 5-FU,substantially reducing toxic side effects of said 5-FU, and acombination thereof, wherein said methylol transfer agent istaurolidine, taurultam, or a mixture thereof.